The history of BIF involves the maturational development and history of B lymphocytes (B cells) of the immunoregulatory system. B cells originate from hematopoietic stem cells and then B cells differentiate into memory cells and plasma cells. It is the plasma cells which secrete immunoglobulin. These transformations are regulated by humoral and cellular factors. Certain human B-lymphocyte cell lines in long-term culture can be stimulated to produce IgM or IgG by co-culture with normal allogeneic T-lymphocytes, by incubation with lymphokine (LK) preparations and by incubation with tumor promoter phorbol myristic acetate (PMA). The presence of T-cell signals were found to be necessary for B cells to mature to immunoglobulin-secreting cells (ISC). One such signal is BIF. BIF has also been known as helper factor, T-cell replacing factor (TRF) and B cells differentiation factor (BDF).
Secretion of antibody is initiated by the binding of antigen to immunoglobulin receptors on the B-lymphocyte surface, together with help from subsets of T cells and accessory cells. This process involves expansion (proliferation) of the triggered B cells and differentiation into plasmacytes, or immunoglobulin-secreting cells (ISC). For many in vitro systems using human lymphocytes, the requirement for helper T cells in induction of B cells can be largely replaced by lymphokines, including growth factors (Muraguchi, et al. (1983) J. Exp. Med. 157: 530; Maizel, et al. (1982) Proc. Nat'l. Acad. Sci. U.S.A. 79: 5998; Okada, et al. (1983) J. Exp. Med. 157: 583) and/or differentiation factors (Insel, et al. (1977) J. Immunol. 118: 2009; Hirano, et al. (1977) J. Immunol. 119: 1235).
A model system for inducing large numbers of human ISC uses the polyclonal activator Staphylococcus aureus strain Cowan I (Sac). The killed bacteria are a potent B-cell mitogen and were originally described as inducing immunoglobulin secretion in the absence of T cells (Ringdon, et al. (1977) Scand. J. Immunol. 6: 1159; Pryjima, et al. (1980) J. Immunol. 124: 656; Dosch, et al. (1980) J. Immunol. 125: 827). Saiki, et al. (1981) (J. Immunol. 127: 1044) confirm that Sac is a T-independent mitogen (DNA synthesis) for peripheral blood B cells, but Saiki, et al. (1981) Supra, and Saiki, et al. (1982) (Cell. Immunol. 70: 301) and others (Falkoff, et al. (1982) J. Immunol., 129: 97) find that Sac is very dependent on T cells for induction of ISC. Sac appears to trigger B cells via an interaction of the bacterial protein A with the antigen-binding (Fab) regions of immunoglobulin receptors, at least in the case of IgM-bearing cells (Romagnani, et al. (1982) J. Immunol. 129: 596).
Since B cells are stimulated by Sac to a high degree of proliferation but seem to require T cells or lymphokine for immunoglobulin secretion, this is an excellent system for the assay of B-cell inducing factor (BIF) which specifically recruits cells into secretion. This invention concerns the purification of BIF for IgM, IgG and IgA production in human blood cells and its relation to interleukin 2 (IL-2).
Human B-lymphocyte lines in long-term culture are models for normal B-cell differentiation. Stimulation of cell line IgM and IgG secretion by coculture with normal allogeneic T lymphocytes (Kishimoto, et al. (1978) Nature (London) 271: 756; Kempner, et al. (1980) Cell Immunol. 55: 32), by incubation with lymphokine preparations (Muraguchi, et al. (1981) J. Immunol. 127: 412; Teranishi, et al. (1982) J. Immunol. 128: 1903; Saiki, et al. Eur. J. Immunol. (1983) 13: 31), and by incubation with tumor promoter phorbol myristic acetate (PMA) (Ralph, et al. (1981) J. Clin. Invest. 68: 1093) have been reported. Human B-cell-inducing factors (BIF) which induce immunoglobulin-secreting cells (ISC) are produced by T lymphocytes in response to mitogens (Hirano, et al. Supra (1977); Saiki, et al. Supra (1981)), allogeneic cells (Friedman, et al. (1979) J. Immunol. 122: 1302), and antigen (Geha, et al. (1973) J. Exp. Med. 138: 1230). T-Cell hybridomas also appear to secrete BIF (Okada, et al. (1981) Proc. Nat'l. Acad. Sci. U.S.A. 78: 7717). With the demonstration that PMA can induce BIF in cultures of peripheral blood T cells (Ralph, et al. (1981) Clin. Immunol. Immunopathol, 22: 340), it became important to determine that the direct stimulatory effect of PMA on ISC formation in B-cell lines was related to the action of BIF (Maurer et al. Cell. Immunol. (1982) 79: 36).